Regulation of the NF-κB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation

Gongxian Liao, Minying Zhang, Edward W. Harhaj, Shao Cong Sun

Research output: Contribution to journalArticle

322 Scopus citations

Abstract

The NF-κB family of transcription factors plays a pivotal role in regulation of diverse biological processes, including immune responses, cell growth, and apoptosis. Activation of NF-κB is mediated by both canonical and noncanonical signaling pathways. Although the canonical pathway has been extensively studied, the mechanism mediating the noncanonical pathway is still poorly understood. Recent studies have identified the NF-κB-inducing kinase (NIK) as a key component of the noncanonical pathway of NF-κB activation; however, how the signaling function of NIK is regulated remains unknown. We report here that one important mechanism of NIK regulation is through its dynamic interaction with the tumor necrosis factor receptor-associated factor 3 (TRAF3). TRAF3 physically associates with NIK via a specific sequence motif located in the N-terminal region of NIK; this molecular interaction appears to target NIK for degradation by the proteasome. Interestingly, induction of noncanonical NF-κB signaling by extracellular signals involves degradation of TRAF3 and the concomitant enhancement of NIK expression. These results suggest that induction of noncanonical NF-κB signaling may involve the rescue of NIK from TRAF3-mediated negative regulation.

Original languageEnglish (US)
Pages (from-to)26243-26250
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number25
DOIs
StatePublished - Jun 18 2004

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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